Leptin Receptor Agonist to Treat Sleep Disordered Breathing

PROJECT SUMMARY/ABSTRACT Obstructive sleep apnea (OSA) and obesity hypoventilation syndrome (OHS) are the most common types of sleep disordered breathing (SDB). OSA is highly prevalent in the United States, affecting 20-40% of the adult population and more than 50% of individuals with obesity. Approximately 20% of individuals with obesity develop OHS defined as daytime hypercapnia and hypoventilation, attributed to the depressed control of breathing. There is no effective pharmacotherapy for OSA and OHS. Our overarching goal is to develop a novel, safe, and effective treatment for sleep disordered breathing (SDB). We have shown that an adipocyte-produced hormone, leptin, which suppresses appetite and increases metabolic rate, stimulates breathing during sleep. Individuals with obesity have high circulating leptin levels, but they are resistant to its beneficial metabolic and respiratory effects. Our laboratory has extensively studies sleep and breathing in mice. We have shown that mice with diet-induced obesity (DIO) develop OHS and OSA, despite high plasma leptin level. Limited permeability of the blood-brain barrier (BBB) for leptin is a key mechanism of leptin resistance. Leptin receptor (LEPRb) agonists engineered to penetrate the BBB are promising therapeutic candidates for SDB treatment. Dr. Laszlo Otvos has developed E1/Aca, a LEPRb agonist, which has been shown to be BBB permeable and superior to leptin for weight loss and metabolic dysfunction in mice and rats. We established a collaboration with Arrevus, which holds a license to E1/Aca, and developed our research plan to characterize E1/Aca’s potential therapeutic benefit in SDB. We will build upon significant preliminary data to demonstrate a proof-of-concept for the use of the leptin receptor agonist, E1/Aca, to treat SDB. Using polysomnography in leptin-resistant diet-induced obese (DIO) mice, two specific aims will be completed to evaluate the acute (SA1) and chronic (SA2) activity of E1/Aca in SDB. Specific Aim 1 will characterize the potency of a single subcutaneous injection of E1/Aca on SDB, compared to leptin. We will evaluate the effect of escalating doses of E1/Aca on (A) OSA severity (the oxygen desaturation index, the apnea- hypopnea index, and minute ventilation during sleep) compared to a fixed dose of leptin; (B) Obesity hypoventilation (arterial CO2 and the hypercapnic ventilatory response awake) compared to a fixed dose of leptin. Specific Aim 2 will characterize the chronic effects of E1/Aca on SDB compared to leptin. We will evaluate the potency and safety of the optimal dose of E1/Aca identified in Aim 1 in DIO mice over a two-week period on (A) SDB severity; (B) Safety by assessing effects of E1/Aca on CNS, cardiovascular, pulmonary, endocrine, and liver toxicity.